Summary of medicine characteristics - ADANIF XL 30 MG TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Adanif XL 30mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 30mg nifedipine.
Excipient with known effect: Each film-coated tablet contains 15 mg Lactose
For the full list of excipients, see Section 6.1.
Prolonged release film-coated tablet.
Pale red, round biconvex tablets.
4.1 Therapeutic indications
For the treatment of all grades of hypertension.
For the prophylaxis of chronic stable angina pectoris either as monotherapy or in combination with a beta-blocker.
4.2 Posology and method of administration
Each prolonged-release tablet contains 30mg nifedipine.
Excipient with known effect: Each film-coated tablet contains 15 mg Lactose For the full list of excipients, see Section 6.1.
4.3 Contraindications
Adanif XL Tablets should not be administered to patients with known hypersensitivity to the active substance, or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients (see Section 4.4 and 6.1).
Adanif XL Tablets should not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within one month of a myocardial infarction.
Adanif XL Tablets should not be used for the treatment of acute attacks of angina.
The safety of Adanif XL Tablets in malignant hypertension has not been established.
Adanif XL Tablets should not be used for secondary prevention of myocardial infarction.
Owing to the duration of action of the formulation, Adanif XL Tablets should not be administered to patients with hepatic impairment.
Adanif XL Tablets should not be administered to patients with a history of gastrointestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract.
Adanif XL Tablets must not be used in patients with a Kock pouch (ileostomy after proctocolectomy ).
Adanif XL Tablets is contra-indicated in patients with inflammatory bowel disease or Crohn's disease.
Adanif XL Tablets should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see Section 4.5).
4.4 Special warnings and precautions for use
Adanif XL Tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.
Caution should be exercised in patients with hypotension as there is a risk of further reduction in blood pressure and care must be exercised in patients with very low blood pressure (severe hypotension with systolic blood pressure less than 90mm Hg).
Adanif XL Tablets should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Adanif XL Tablets should be reserved for women with severe hypertension who are unresponsive to standard therapy (see Section 4.6).
Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. magnesium sulphate, owing to the possibility of an excessive fall in blood pressure, which could harm both mother and foetus. For further information regarding use in pregnancy, refer to Section 4.6.
Adanif XL Tablets is not recommended for use during breastfeeding because nifedipine has been reported to be excreted in human milk and the effects of nifedipine exposure to the infant are not known (see Section 4.6).
In patients with impaired liver function careful monitoring and, in severe cases, a dose reduction may be necessary.
Adanif XL Tablets may be used in combination with beta-blocking drugs and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Adanif XL Tablets will not prevent possible rebound effects after cessation of other antihypertensive therapy.
Adanif XL Tablets should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.
Diabetic patients taking Adanif XL Tablets may require adjustment of their control.
In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.
Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine (see Section 4.5).
Drugs, which are known inhibitors of the cytochrome P450 3A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:
– macrolide antibiotics (e.g., erythromycin)
– anti-HIV protease inhibitors (e.g., ritonavir)
– azole antimycotics (e.g., ketoconazole)
– the antidepressants, nefazodone and fluoxetine
– quinupristin/dalfopristin
– valproic acid
– cimetidine
Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.
As the outer membrane of the Adanif XL Tablets is not digested, what appears to be the complete tablet may be seen in the toilet or associated with the patient's stools. Also, as a result of this, care should be exercised when administering Adanif XL Tablets to patients, as obstructive symptoms may occur. Bezoars can occur in very rare cases and may require surgical intervention.
In single cases, obstructive symptoms have been described without known history of gastrointestinal disorders.
A false positive effect may be experienced when performing a barium contrast x-ray.
For use in special populations see Section 4.2.
Adanif XL Tablets contains Lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Drugs that affect nifedipine
Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine.
The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs:
Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon coadministration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contraindicated (see Section 4.3).
Upon co-administration of known inhibitors of the cytochrome P450 3A4 system, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Sections 4.2 and 4.4). In the majority of these cases, no formal studies to assess the potential for a drug interaction between nifedipine and the drug(s) listed have been undertaken, thus far.
Drugs increasing nifedipine exposure:
– macrolide antibiotics (e.g., erythromycin)
– anti-HIV protease inhibitors (e.g., ritonavir)
– azole anti-mycotics (e.g., ketoconazole)
– fluoxetine
– nefazodone
– quinupristin/dalfopristin
– cisapride
– valproic acid
– cimetidine
– diltiazem
Upon co-administration of inducers of the cytochrome P450 3A4 system, the clinical response to nifedipine should be monitored and, if necessary, an increase in the nifedipine dose considered. If the dose of nifedipine is increased during coadministration of both drugs, a reduction of the nifedipine dose should be considered when the treatment is discontinued.
Drugs decreasing nifedipine exposure:
– rifampicin (see above)
– phenytoin
– carbamazepine
– phenobarbital
Effects of nifedipine on other drugs
Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives.
When nifedipine is administered simultaneously with B-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases.
Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and, hence, an increase in the plasma digoxin level. The patient should therefore be subjected to precautionary checks for symptoms of digoxin overdosage and, if necessary, the glycoside dose should be reduced.
Quinidine: Co-administration of nifedipine with quinidine may lower plasma quinidine levels, and after discontinuation of nifedipine, a distinct increase in plasma quinidine levels may be observed in individual cases. Consequently, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Blood pressure should be carefully monitored and, if necessary, the dose of nifedipine should be decreased.
Tacrolimus: Tacrolimus is metabolised via the cytochrome P450 3A4 system. Published data indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration of both drugs, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.
Drug food interactions
Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nifedipine due to a decreased first pass metabolism or reduced clearance. As a consequence, the blood pressure lowering effect of nifedipine may be increased. After regular intake of grapefruit juice, this effect may last for at least three days after the last ingestion of grapefruit juice. Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking nifedipine (see Section 4.2).
Other forms of interaction
Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid, falsely. However, HPLC measurements are unaffected.
4.6 Fertility, pregnancy and lactation
Pregnancy
Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine (see Section 4.4).
In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see Section 5.3).
There are no adequate well controlled studies in pregnant women.
From the clinical evidence available a specific prenatal risk has not been identified, although an increase in perinatal asphyxia, caesarean delivery, as well as prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment, or to a specific drug effect.
The available information is inadequate to rule out adverse drug effects on the unborn and newborn child. Therefore any use in pregnancy requires a very careful individual risk benefit assessment and should only be considered if all other treatment options are either not indicated or have failed to be efficacious.
Acute pulmonary oedema has been observed when calcium channel blockers, among others nifedipine, have been used as tocolytic agent during pregnancy (see section 4.8), especially in cases of multiple pregnancy (twins or more), with the intravenous route and/or concomitant use of beta-2 agonists.
Breast-feeding
Nifedipine is excreted in the breast milk. The nifedipine concentration in the milk is almost comparable with mother serum concentration. For immediate release formulations, it is proposed to delay breastfeeding or milk expression for 3 to 4 hours after drug administration to decrease the nifedipine exposure to the infant (see Section 4.4).
Fertility
In single cases of in vitro fertilisation calcium antagonists like nifedipine have been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function. In those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.
4.7 Effects on ability to drive and use machines
Reactions to the drug, which vary in intensity from individual to individual, may impair the ability to drive or to operate machinery (see Section 4.8). This applies particularly at the start of treatment, on changing the medication and in combination with alcohol.
4.8 Undesirable effects
Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n = 2,661; placebo n = 1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n = 3,825; placebo n = 3,840) are listed below:
ADRs listed under „common“ were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).
The frequencies of ADRs reported with nifedipine-containing products are summarised in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100) and rare (>1/10,000 to < 1/1,000).
The ADRs identified only during the ongoing post marketing surveillance,and for which a frequency could not be estimated, are listed under “Not Known”.
Common | Uncommon | Rare | Not Known |
Blood and Lymphatic System Disorders | |||
Agranulocytosis Leucopenia | |||
Immune System Disorders | |||
Allergic reaction Allergic oedema/angioedema (incl. larynx oedema*) | Pruritus Urticaria Rash | Anaphylactic/ anaphylactoid reaction | |
Psychiatric Disorders | |||
Anxiety reactions Sleep disorders | |||
Metabolism and Nutrition Disorders | |||
Hyperglycaemia | |||
Nervous System Disorders | |||
Headache | Vertigo Migraine Dizziness Tremor | Par-/Dysaesthesia | Hypoaesthesia Somnolence |
Eye Disorders | |||
Visual disturbances | Eye pain |
Cardiac Disorders
Tachycardia Palpitations | Chest pain (Angina pectoris) | ||
Vascular Disorders | |||
Oedema (incl. peripheral oedema) Vasodilatation | Hypotension Syncope | ||
Respiratory Thoracic and Mediastinal Disorders | |||
Nosebleed Nasal congestion | Dyspnoea Pulmonary oedema | ||
Gastrointestinal Disorders | |||
Constipation | Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Dry mouth | Gingival hyperplasia | Bezoar Dysphagia Intestinal obstruction Intestinal ulcer Vomiting Gastroesophageal sphincter insufficiency |
Hepatobiliary Disorders | |||
Transient increase in liver enzymes | Jaundice | ||
Skin and Subcutaneous Tissue Disorders | |||
Erythema | Toxic Epidermal Necrolysis Photosensitivity allergic reaction Palpable purpura | ||
Musculoskeletal and | Connective Tissue Disorders | ||
Muscle cramps Joint swelling | Arthralgia Myalgia | ||
Renal and Urinary | disorders | ||
Polyuria Dysuria | |||
Reproductive System and Breast Disord | ers | ||
Erectile dysfunction |
General Disorders and Administration Site Conditions
Feeling unwell | Unspecific pain Chills |
* may result in life-threatening outcome
cases have been reported when used as tocolytic during pregnancy (see section 4.6)
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseSymptoms
The following symptoms are observed in cases of severe nifedipine intoxication:
Disturbances of consciousness to the point of coma, a drop in blood pressure, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.
Treatment
As far as treatment is concerned, elimination of nifedipine and the restoration of stable cardiovascular conditions have priority. Elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance. The benefit of gastric decontamination is uncertain.
1. Consider activated charcoal (50g for adults, 1g/kg for children) if the patient presents within 1 hour of ingestion of a potentially toxic amount.
Although it may seem reasonable to assume that late administration of activated charcoal may be beneficial for sustained release (SR, MR) preparations there is no evidence to support this.
2. Alternatively consider gastric lavage in adults within 1 hour of a potentially lifethreatening overdose.
3. Consider further doses of activated charcoal every 4 hours if a clinically significant amount of a sustained release preparation has been ingested with a single dose of an osmotic laxative (e.g. sorbitol, lactulose or magnesium sulphate).
4. Asymptomatic patients should be observed for at least 4 hours after ingestion and for 12 hours if a sustained release preparation has been taken.
Haemodialysis serves no purpose as nifedipine is not dialysable, but plasmaspheresis is advisable (high plasma protein binding, relatively low volume of distribution). Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with calcium (10–20ml of a 10% calcium gluconate solution administered intravenously over 5–10 minutes). If the effects are inadequate, the treatment can be continued, with ECG monitoring. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient's response.
Symptomatic bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker, as required. Additional fluids should be administered with caution to avoid cardiac overload.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective calcium channel blockers with mainly vascular effect, dihydropyridine derivatives
ATC code: C08 CA05
Mechanism of action
Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell.
Pharmacodynamic effects
As a specific and potent calcium antagonist, nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. The main action of nifedipine is to relax arterial smooth muscle, both in the coronary and peripheral circulation. The Adanif XL Tablets is formulated to achieve controlled delivery of nifedipine in a release profile sufficient to enable once-daily administration to be effective in clinical use.
Clinical efficacy and safety
In hypertension, the main action of nifedipine is to cause peripheral vasodilatation and thus reduce peripheral resistance. Nifedipine administered once-daily provides 24-hour control of raised blood pressure. Nifedipine causes reduction in blood pressure such that the percentage lowering is proportional to its initial level. In normotensive individuals, nifedipine has little or no effect on blood pressure.
In angina, Adanif XL Tablets reduces peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume, whilst decreasing after-load. Additionally, nifedipine dilates submaximally both clear and atherosclerotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium. Nifedipine reduces the frequency of painful attacks and the ischaemic ECG changes irrespective of the relative contribution from coronary artery spasm or atherosclerosis.
In a multi-national, randomised, double-blind, prospective study involving 6321 hypertensive patients with at least one additional risk factor followed over 3 to 4.8 years, Adanif XL 30 and 60 Tablets (nifedipine GITS) were shown to reduce blood pressure to a comparable degree as a standard diuretic combination.
Paediatric population:
Limited information on comparison of nifedipine with other antihypertensives is available for both acute hypertension and long-term hypertension with different formulations in different dosages. Antihypertensive effects of nifedipine have been demonstrated but dose recommendations, long term safety and effect on cardiovascular outcome remain unestablished. Paediatric dosing forms are lacking.
5.2 Pharmacokinetic properties
General characteristics:
Adanif XL Tablets are formulated to provide nifedipine at an approximately constant rate over 24 hours. Nifedipine is released from the tablet at a zero-order rate by a membrane-controlled, osmotic push-pull process. The pharmacokinetic profile of this formulation is characterized by low peak-trough fluctuation. 0–24 hour plasma concentration versus time profiles at steady state are plateau-like, rendering the Adanif XL Tablets appropriate for once-a-day administration.
The delivery rate is independent of gastrointestinal pH or motility. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the faeces as an insoluble shell.
Absorption
Orally administered nifedipine is almost completely absorbed in the gastro-intestinal tract. The systemic availability of orally administered nifedipine immediate release formulations (nifedipine capsules) is 45–56% owing to a first pass effect. At steadystate, the bioavailability of Adanif XL Tablets ranges from 68–86% relative to Nifedipine capsules. Administration in the presence of food slightly alters the early rate of absorption but does not influence the extent of drug availability.
Distribution
Nifedipine is about 95% bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.
Biotransformation
After oral administration, nifedipine is metabolised in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity. Nifedipine is eliminated in the form of its metabolites, predominantly via the kidneys, with approximately 5–15% being excreted via the bile in the faeces. Nonmetabolised nifedipine can be detected only in traces (below 0.1%) in the urine.
Elimination
The terminal elimination half-life is 1.7 to 3.4 hours in conventional formulations (nifedipine capsules). The terminal half-life following Adanif XL Tablets administration does not represent a meaningful parameter as a plateau-like plasma concentration is maintained during release from the tablets and absorption. After release and absorption of the last dose the plasma concentration finally declines with an elimination half-life as seen in conventional formulations.
Characteristics in patients:
There are no significant differences in the pharmacokinetics of nifedipine between healthy subjects and subjects with renal impairment. Therefore, dosage adjustment is not needed in these patients.
In patients with hepatic impairment, the elimination half-life is distinctly prolonged and the total clearance is reduced. Owing to the duration of action of the formulation, Adanif XL Tablets should not be administered in these patients.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet Core
Povidone K30
Talc
Hypromellose
Carbomer 974P
Anhydrous colloidal silica
Magnesium stearate
Lactose monohydrate
Coating
Ferric oxide (red) (E172)
Titanium dioxide (E171)
Macrogol 4000
Eudragit “E”
Hypromellose
Magnesium stearate
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Do not store above 25oC. Store in the original package in order to protect from light.
6.5 Nature and contents of container
28 tablets in PVC/PVdC – Aluminium blisters.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo additional information.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements